Abstract:

>Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8+CGRP+ nociceptor neurons are juxtaposed with and signal to intestinal goblet cells to drive mucus secretion and gut protection. Nociceptor ablation led to decreased mucus thickness and dysbiosis, while chemogenetic nociceptor activation or capsaicin treatment induced mucus growth. Mouse and human goblet cells expressed Ramp1, receptor for the neuropeptide CGRP. Nociceptors signal via the CGRP-Ramp1 pathway to induce rapid goblet cell emptying and mucus secretion. Notably, commensal microbes activated nociceptors to control homeostatic CGRP release. In the absence of nociceptors or epithelial Ramp1, mice showed increased epithelial stress and susceptibility to colitis. Conversely, CGRP administration protected nociceptor-ablated mice against colitis. Our findings demonstrate a neuron-goblet cell axis that orchestrates gut mucosal barrier protection.

Capsaicin produced the effect, though not directly on the TRPV1 (aka "capsaicin/vanilloid receptor"). But this suggests that TRPV1 is likely the "nociceptor" being described here, and CGRP is produced downstream which then mediates the rest of the effect (likely including pain)

CGRP is believed to be the major downstream mediator of migraines, as CGRP inhibitors (receptor antagonists) tend to provide faster relief of symptoms than 5-HT1B / 5-HT1D agonists like the tryprans which reduce CGRP production but don't block the already existing CGRP from their receptors. Whether or not CGRP from the gut can contribute to migraine would be an interesting subject for future study, as gut problems are known to be fairly comorbid with headaches